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. 2023 Oct 30;196(1):71-84.
doi: 10.1093/toxsci/kfad083.

Immunotoxicity of N-butylbenzenesulfonamide: impacts on immune function in adult mice and developmentally exposed rats

Victor J Johnson  1 , Cynthia V Rider  2 , Michael I Luster  1 , Amy Brix  3 , Gary R Burleson  1 , Michelle Cora  2 , Susan A Elmore  2 , Rachel P Frawley  2 , Franklin R Lopez  4 , Esra Mutlu  2 , Keith R Shockley  2   5 , Jessica Pierfelice  6 , Brian Burback  6 , Caroll A Co  7 , Dori R Germolec  2
Affiliations

Immunotoxicity of N-butylbenzenesulfonamide: impacts on immune function in adult mice and developmentally exposed rats

Victor J Johnson et al. Toxicol Sci. .

Abstract

N-butylbenzenesulfonamide (NBBS) is a high-production volume plasticizer that is an emerging contaminant of concern for environmental and human health. To understand the risks and health effects of exposure to NBBS, studies were conducted in adult-exposed mice and developmentally exposed rats to evaluate the potential for NBBS to modulate the immune system. Beginning between 8 and 9 weeks of age, dosed feed containing NBBS at concentrations of 0, 313, 625, 1250, 2500, and 5000 ppm was continuously provided to B6C3F1/N female mice for 28 days. Dosed feed was also continuously provided to time-mated Harlan Sprague Dawley (Sprague Dawley SD) rats at concentrations of 0-, 250-, 500-, and 1000-ppm NBBS from gestation day 6 to postnatal day 28 and in F1 rats until 11-14 weeks of age. Functional assessments of innate, humoral, and cell-mediated immunity were conducted in adult female mice and F1 rats following exposure to NBBS. In female mice, NBBS treatment suppressed the antibody-forming cell (AFC) response to SRBC with small increases in T-cell responses and natural killer (NK)-cell activity. In developmentally exposed rats, NBBS treatment-related immune effects were sex dependent. A positive trend in NK-cell activity occurred in male F1 rats while a negative trend occurred in female F1 rats. The AFC response to SRBC was decreased in female F1 rats but not in male F1 rats. These data provide evidence that oral exposure to NBBS has the potential to produce immunomodulatory effects on both innate and adaptive immune responses, and these effects appear to have some dependence on species, sex, and period of exposure (developmental vs adult).

Keywords: N-butylbenzenesulfonamide; T-dependent antibody response; benzosulfonamides; developmental immunotoxicity; immunotoxicity testing; natural killer cell activity.

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Figures

Figure 1.
Figure 1.
Popliteal lymph node histology in female F1 rats following developmental exposure to NBBS. A, H&E section of popliteal lymph node from a vehicle control female rat (227) showing scattered black pigment (arrows) and mast cells (arrowheads) within the medullary sinuses and cords. B, H&E section of popliteal lymph node from a female rat (333) treated with 1000-ppm NBBS. There is a lack of black pigment within the medullary sinuses and cords. C, H&E section of popliteal lymph node from a female rat (334) treated with 1000-ppm NBBS. The medullary cords and sinuses are filled with pale foamy macrophages and numerous neutrophils (arrows). Abbreviations: NBBS, N-butylbenzenesulfonamide; H&E, Hematoxylin and Eosin.
Figure 2.
Figure 2.
NBBS treatment suppresses the AFC response to SRBC. Data are expressed as (A) spleen cellularity in mice, (B) AFC per 106 splenocytes in mice, (C) AFC per spleen in mice, (D) spleen cellularity in male F1 rats, (E) AFC per 106 splenocytes in male F1 rats, (F) AFC per spleen in male F1 rats, (G) spleen cellularity in female F1 rats, (H) AFC per 106 splenocytes in female F1 rats, and (I) AFC per spleen in female F1 rats. ↓Indicates a significant negative trend with increasing NBBS dose (p < .05). Significantly different from the vehicle control group at *p < .05 or **p < .01. Abbreviations: AFC, antibody-forming cell; CPS, cyclophosphamide (50 mg/kg in mice or 15 mg/kg in F1 rats); NBBS, N-butylbenzenesulfonamide.
Figure 3.
Figure 3.
NBBS treatment modulated NK cell activity in mice and rats. NK cells isolated from the spleen were mixed at E:T ratios with YAC-1 target cells of (A) 6.25:1, (B) 12.5:1, and (C) 25:1 in female mice, (D) 12.5:1, (E) 25:1, and (F) 50:1 in male F1 rats, and (G) 12.5:1, (H) 25:1, and (I) 50:1 in female F1 rats. NK killing activity was expressed as % cytotoxicity of the total target cells. Indicates a significant ↑positive or ↓negative trend with increasing NBBS dose (p < .05). Significantly different from the vehicle control group at *p < .05 or **p < .01. Abbreviations: E:T, effector cell:target cell ratio; NBBS, N-butylbenzenesulfonamide; NK, natural killer.
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